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dc.contributor.authorKalash, Leen
dc.contributor.authorVal García, Cristina
dc.contributor.authorAzuaje Guerrero, Jhonny Alberto
dc.contributor.authorLoza García, María Isabel
dc.contributor.authorSvensson, Fredrik
dc.contributor.authorZoufir, Azedine
dc.contributor.authorMervin, Lewis
dc.contributor.authorLadds, Graham
dc.contributor.authorBrea Floriani, José Manuel
dc.contributor.authorGlen, Robert
dc.contributor.authorSotelo Pérez, Eddy
dc.contributor.authorBender, Andreas
dc.date.accessioned2019-09-11T11:00:10Z
dc.date.available2019-09-11T11:00:10Z
dc.date.issued2017
dc.identifier.citationKalash, L., Val, C., Azuaje, J., Loza, M., Svensson, F., & Zoufir, A. et al. (2017). Computer-aided design of multi-target ligands at A1R, A2AR and PDE10A, key proteins in neurodegenerative diseases. Journal Of Cheminformatics, 9(1). doi: 10.1186/s13321-017-0249-4
dc.identifier.issn1758-2946
dc.identifier.urihttp://hdl.handle.net/10347/19760
dc.description.abstractCompounds designed to display polypharmacology may have utility in treating complex diseases, where activity at multiple targets is required to produce a clinical efect. In particular, suitable compounds may be useful in treating neurodegenerative diseases by promoting neuronal survival in a synergistic manner via their multi-target activity at the adenosine A1 and A2A receptors (A1R and A2AR) and phosphodiesterase 10A (PDE10A), which modulate intracellular cAMP levels. Hence, in this work we describe a computational method for the design of synthetically feasible ligands that bind to A1 and A2A receptors and inhibit phosphodiesterase 10A (PDE10A), involving a retrosynthetic approach employing in silico target prediction and docking, which may be generally applicable to multi-target compound design at several target classes. This approach has identifed 2-aminopyridine-3-carbonitriles as the frst multi-target ligands at A1R, A2AR and PDE10A, by showing agreement between the ligand and structure based predictions at these targets. The series were synthesized via an efcient one-pot scheme and validated pharmacologically as A1R/A2AR–PDE10A ligands, with IC50 values of 2.4–10.0 μM at PDE10A and Ki values of 34–294 nM at A1R and/or A2AR. Furthermore, selectivity profling of the synthesized 2-amino-pyridin-3-carbonitriles against other subtypes of both protein families showed that the multi-target ligand 8 exhibited a minimum of twofold selectivity over all tested oftargets. In addition, both compounds 8 and 16 exhibited the desired multi-target profle, which could be considered for further functional efcacy assessment, analog modifcation for the improvement of selectivity towards A1R, A2AR and PDE10A collectively, and evaluation of their potential synergy in modulating cAMP levels
dc.description.sponsorshipLK thanks the IDB Cambridge International Scholarship for support. This work was fnancially supported by the ERC Starting Grant to AB (No. 336159), the Consellería de Cultura, Educación e Ordenación Universitaria of the Galician Government: (Grant: GPC2014/03), Centro singular de investigación de Galicia accreditation 2016–2019 (ED431G/09) and the European Regional Development Fund (ERDF)
dc.language.isoeng
dc.publisherBioMed Central
dc.relationinfo:eu-repo/grantAgreement/EC/FP7/336159
dc.rights© The Author(s) 2017. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated
dc.rightsAtribución 4.0 Internacional
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectMulti-target ligands
dc.subjectAdenosine receptor ligands
dc.subjectPDE10A inhibitors
dc.subjectTarget prediction
dc.subjectDrug design
dc.subjectDocking
dc.subjectQSAR
dc.titleComputer-aided design of multi-target ligands at A1R, A2AR and PDE10A, key proteins in neurodegenerative diseases
dc.typeinfo:eu-repo/semantics/article
dc.identifier.DOI10.1186/s13321-017-0249-4
dc.relation.publisherversionhttps://doi.org/10.1186/s13321-017-0249-4
dc.type.versioninfo:eu-repo/semantics/publishedVersion
dc.rights.accessrightsinfo:eu-repo/semantics/openAccess
dc.contributor.affiliationUniversidade de Santiago de Compostela. Centro de Investigación en Medicina Molecular e Enfermidades Crónicas
dc.contributor.affiliationUniversidade de Santiago de Compostela. Centro de Investigación en Química Biolóxica e Materiais Moleculares
dc.description.peerreviewedSI


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© The Author(s) 2017. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated
Except where otherwise noted, this item's license is described as  © The Author(s) 2017. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated





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